Yang et al. (2014) described that TGF-β signaling induces lipogenesis-associated genes and suppresses β-oxidation-associated factors to promote lipid accumulation in hepatocytes upon palmitate supplementation in vitro. In vivo, Smad3-deficient mice fed a HFD were resistant to obesity and hepatic steatosis, which illustrated that the TGF-β/Smad3 signaling pathway plays a crucial role in regulating energy homeostasis (Yadav et al., 2011). This evidence concerns the gene SMAD3 and obesity due to melanocortin 4 receptor deficiency.